Repression of Beta-catenin Signaling by PPAR Gamma Ligands

Overview

Journal Eur J Pharmacol

Specialty Pharmacology

Date 2010 Mar 23

PMID 20303941

Citations 44

Authors

Desheng Lu

Dennis A Carson

Affiliations

Soon will be listed here.

Abstract

Aberrant activation of the Wnt/beta-catenin signaling pathway plays a crucial role in oncogenesis of various human malignancies. It has been demonstrated that there is a direct interaction between beta-catenin and PPAR gamma. Here we examined the effects of fifteen reported PPAR ligands in a reporter gene assay that is dependent on beta-catenin activation of TCF/LEF transcription factors; only the thiazolidinedione PPAR gamma agonists troglitazone, rosiglitazone and pioglitazone, and a non-thiazolidinedione PPAR gamma activator GW1929 inhibited beta-catenin-induced transcription in a PPAR gamma dependent fashion. The results from mammalian one-hybrid experiments showed that functional PPAR gamma was necessary for ligand-dependent inhibition of beta-catenin transactivation. However, a PPAR gamma activator Fmoc-Leu could not repress beta-catenin-mediated signaling and its transactivation activity. These results indicate that activation of PPAR gamma is necessary, but not sufficient, for the beta-catenin antagonistic activity of a PPAR gamma agonist, and that the inhibitory compounds interfere directly with beta-catenin transactivation activity.

Citing Articles

Turkish coffee has an antitumor effect on breast cancer cells in vitro and in vivo.

Amin M, Abdelmohsen U, Samra Y Nutr Metab (Lond). 2024; 21(1):73.

PMID: 39272080 PMC: 11396339. DOI: 10.1186/s12986-024-00846-4.

High-Intensity Focused Ultrasound Increases Facial Adipogenesis in a Swine Model via Modulation of Adipose-Derived Stem Cell Cilia.

Byun K, Kim H, Oh S, Batsukh S, Lee S, Oh M Int J Mol Sci. 2024; 25(14).

PMID: 39062891 PMC: 11277104. DOI: 10.3390/ijms25147648.

CTNNB1 in neurodevelopmental disorders.

Zhuang W, Ye T, Wang W, Song W, Tan T Front Psychiatry. 2023; 14:1143328.

PMID: 37009120 PMC: 10061110. DOI: 10.3389/fpsyt.2023.1143328.

Simvastatin Improves Benign Prostatic Hyperplasia: Role of Peroxisome-Proliferator-Activated Receptor-γ and Classic WNT/β-Catenin Pathway.

Wang Z, Yang S, Li Y, Zhou Y, Liu D, Liu J Int J Mol Sci. 2023; 24(5).

PMID: 36902342 PMC: 10003121. DOI: 10.3390/ijms24054911.

Pro-inflammatory role of Wnt/β-catenin signaling in endothelial dysfunction.

Wadey K, Somos A, Leyden G, Blythe H, Chan J, Hutchinson L Front Cardiovasc Med. 2023; 9:1059124.

PMID: 36794234 PMC: 9923234. DOI: 10.3389/fcvm.2022.1059124.

References

Debril M, Renaud J, Fajas L, Auwerx J . The pleiotropic functions of peroxisome proliferator-activated receptor gamma. J Mol Med (Berl). 2001; 79(1):30-47. DOI: 10.1007/s001090000145. View

Pascual G, Fong A, Ogawa S, Gamliel A, Li A, Perissi V . A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature. 2005; 437(7059):759-63. PMC: 1464798. DOI: 10.1038/nature03988. View

Lehmann J, Moore L, Wilkison W, Willson T, Kliewer S . An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem. 1995; 270(22):12953-6. DOI: 10.1074/jbc.270.22.12953. View

Kliewer S, Lenhard J, Willson T, Patel I, Morris D, Lehmann J . A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell. 1995; 83(5):813-9. DOI: 10.1016/0092-8674(95)90194-9. View

Shtutman M, Zhurinsky J, Simcha I, Albanese C, DAmico M, Pestell R . The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci U S A. 1999; 96(10):5522-7. PMC: 21892. DOI: 10.1073/pnas.96.10.5522. View

Li M, Pascual G, Glass C . Peroxisome proliferator-activated receptor gamma-dependent repression of the inducible nitric oxide synthase gene. Mol Cell Biol. 2000; 20(13):4699-707. PMC: 85890. DOI: 10.1128/MCB.20.13.4699-4707.2000. View

Girnun G, Smith W, Drori S, Sarraf P, Mueller E, Eng C . APC-dependent suppression of colon carcinogenesis by PPARgamma. Proc Natl Acad Sci U S A. 2002; 99(21):13771-6. PMC: 129773. DOI: 10.1073/pnas.162480299. View

Kliewer S, Xu H, Lambert M, Willson T . Peroxisome proliferator-activated receptors: from genes to physiology. Recent Prog Horm Res. 2001; 56:239-63. DOI: 10.1210/rp.56.1.239. View

Koeffler H . Peroxisome proliferator-activated receptor gamma and cancers. Clin Cancer Res. 2003; 9(1):1-9. View

10.

Clevers H . Wnt/beta-catenin signaling in development and disease. Cell. 2006; 127(3):469-80. DOI: 10.1016/j.cell.2006.10.018. View

11.

Moon R, Kohn A, De Ferrari G, Kaykas A . WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet. 2004; 5(9):691-701. DOI: 10.1038/nrg1427. View

12.

Wang C, Fu M, DAmico M, Albanese C, Zhou J, Brownlee M . Inhibition of cellular proliferation through IkappaB kinase-independent and peroxisome proliferator-activated receptor gamma-dependent repression of cyclin D1. Mol Cell Biol. 2001; 21(9):3057-70. PMC: 86934. DOI: 10.1128/MCB.21.9.3057-3070.2001. View

13.

Lu D, Zhao Y, Tawatao R, Cottam H, Sen M, Leoni L . Activation of the Wnt signaling pathway in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 2004; 101(9):3118-23. PMC: 365753. DOI: 10.1073/pnas.0308648100. View

14.

Xiao J, Ghosn C, Hinchman C, Forbes C, Wang J, Snider N . Adenomatous polyposis coli (APC)-independent regulation of beta-catenin degradation via a retinoid X receptor-mediated pathway. J Biol Chem. 2003; 278(32):29954-62. DOI: 10.1074/jbc.M304761200. View

15.

Jansson E, Are A, Greicius G, Kuo I, Kelly D, Arulampalam V . The Wnt/beta-catenin signaling pathway targets PPARgamma activity in colon cancer cells. Proc Natl Acad Sci U S A. 2005; 102(5):1460-5. PMC: 547827. DOI: 10.1073/pnas.0405928102. View

16.

Lehrke M, Lazar M . The many faces of PPARgamma. Cell. 2005; 123(6):993-9. DOI: 10.1016/j.cell.2005.11.026. View

17.

Kliewer S, Sundseth S, Jones S, Brown P, Wisely G, Koble C . Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc Natl Acad Sci U S A. 1997; 94(9):4318-23. PMC: 20720. DOI: 10.1073/pnas.94.9.4318. View

18.

Lu D, Cottam H, Corr M, Carson D . Repression of beta-catenin function in malignant cells by nonsteroidal antiinflammatory drugs. Proc Natl Acad Sci U S A. 2005; 102(51):18567-71. PMC: 1317972. DOI: 10.1073/pnas.0509316102. View

19.

Grommes C, Landreth G, Heneka M . Antineoplastic effects of peroxisome proliferator-activated receptor gamma agonists. Lancet Oncol. 2004; 5(7):419-29. DOI: 10.1016/S1470-2045(04)01509-8. View

20.

Altiok S, Xu M, Spiegelman B . PPARgamma induces cell cycle withdrawal: inhibition of E2F/DP DNA-binding activity via down-regulation of PP2A. Genes Dev. 1997; 11(15):1987-98. PMC: 316411. DOI: 10.1101/gad.11.15.1987. View